Treatment of pathological chronic pain remains one of the top clinical problems yet to be solved. Clinical literature, published soon after the First nd Second World Wars, describes numerous cases of soldiers shot through the head, with damage restricted to the postcentral gyrus, who lost the ability to experience pain in some part of the body. These cases, as well as reports of surgical ablations in human chronic pain patients, suggest that some part of the primary somatosensory cortex (SI) is critically involved in pain generation. A cortical region with such power over pain perception would make an attractive target for clinical suppression of pathological pain. Recently, an SI region was found within cytoarchitectonic area 3a that does preferentially respond to noxious stimulation in a manner closely resembling human experience of second or slow pain. The goal of this project is to test the hypothesis that pain loss experienced by humans with parietal cortical damage can be reproduced experimentally by selective inactivation of this nociresponsive region of area 3a. In the present study, which will be conducted in trained squirrel monkeys, the area 3a region revealed by optical imaging to respond selectively to thermonoxious stimulation of the contralateral hand will be reversibly inactivated in test sessions by topical application of GABA agonist muscimol or by local cortical cooling. In a subset of monkeys this nociresponsive area 3a region will be inactivated irreversibly - by ibotenic acid injection - in order to observe long-term effects of the loss of this cortical region. The subject's pain sensibility will be measured o a behavioral operant pain escape task before and after the area 3a inactivation. The prediction is that area 3a inactivation will prominently reduce, if not completely abolish, aversive pain that would normally accompany noxious stimuli applied to the contralateral hand. Unambiguous experimental confirmation or rejection of this hypothesis is of extremely high clinical relevance - the easy accessibility of the nociresponsive neurons of area 3a makes them a most attractive target for minimally invasive and highly selective therapeutic strategies for the amelioration/elimination of pathological pain in human patients. PUBLIC HEALTH RELEVANCE: The project will provide novel experimental information that will greatly enhance the specificity and effectiveness of clinical procedures that use cerebral cortical stimulation or suppression for the treatment of chronic pain in humans. Experimental demonstration that inactivation of cortical area 3a can alleviate pain will make this cortical regin a most attractive target for minimally invasive and highly selective therapeutic strategies for the amelioration/elimination of pathological pain in human patients.